Maternal lifetime exposures to perturbations such as stress, infection, malnutrition, and advanced age have been linked with an increased risk for offspring disease, including a strong association with neuropsychiatric disorders. While maternal insults during pregnancy can directly impact fetal development, the mechanisms by which lifelong experiences can alter germ cell programming and affect offspring neurodevelopment are not known. Surprisingly few animal models have been developed to examine programming mechanisms of preconception perturbations. In this proposal, we utilize our mouse model of maternal preconception stress (MPS) in which female, but not male, offspring present with elevated stress sensitivity, to examine the sex- specific mechanisms contributing to neurodevelopmental programming. Based on our exciting published and preliminary data, we hypothesize that MPS imparts changes in oocyte stored maternal mRNAs that interact during blastocyst and placental development to program sex-specific changes in the developing hypothalamus. Our hypothesis will be tested in this proposal and examined at 3 distinct mechanistic levels: the oocyte, the placenta, and the hypothalamus. Sex differences in the placenta are likely to produce sex-specific trans- placental signals to the developing brain and begin with sex chromosomes. Our studies and others have identified X-linked genes that are expressed at higher levels in the female placenta. Through a genome-wide screen following maternal stress, we identified the X-linked gene, OGT, as causal in programming a sex- specific stress phenotype. Placental OGT is poised to respond to changes in the environment that are important to the developing embryo, ultimately serving as a sex-specific regulator of hypothalamic development. Therefore, our proposal will focus on defining mechanisms contributing to MPS programming examining the: 1) oocyte: To identify the lasting molecular changes that occur in response to preconception stress that are present at fertilization and their necessity for reproducing the female offspring phenotype, 2) placenta: To determine the maternal preconception stress sex-specific mechanisms involved in the female offspring phenotype focusing on the placental contribution, and 3) hypothalamus: To determine the sex-specific hypothalamic programming changes following maternal preconception stress and the role this plays as an underlying factor in female neuropsychiatric disease risk.